Mechanisms and modulation of sepsis-induced immune dysfunction in children

Abstract

Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. Sepsis has a direct impact on the immune system due to adverse alteration of the production, maturation, function, and apoptosis of immune cells. Dysregulation in both the innate and adaptive immune responses during sepsis leads to a range of phenotypes consisting of both hyperinflammation and immunosuppression that can result in immunoparalysis. In this review, we discuss components of immune dysregulation in sepsis, biomarkers and functional immune assays to aid in immunophenotyping patients, and evolving immunomodulatory therapies. Important research gaps for the future include: (1) Defining how age, host factors including prior exposures, and genetics impact the trajectory of sepsis in children, (2) Developing tools for rapid assessment of immune function in sepsis, and (3) Assessing how evolving pediatric sepsis endotypes respond differently to immunomodulation. Although multiple promising immunomodulatory agents exist or are in development, access to rapid immunophenotyping will be needed to identify which children are most likely to benefit from which therapy. Advancements in the ability to perform multidimensional endotyping will be key to developing a personalized approach to children with sepsis. IMPACT: Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. The resulting spectrum of immunoparalysis that can occur due to sepsis can increase morbidity and mortality in children and adults. This narrative review summarizes the current literature surrounding biomarkers and functional immunologic assays for immune dysregulation in sepsis, with a focus on immunomodulatory therapies that have been evaluated in sepsis. A precision approach toward diagnostic endotyping and therapeutics, including gene expression, will allow for optimal clinical trials to evaluate the efficacy of individualized and targeted treatments for pediatric sepsis.

Figure 1:. Pathways of immune dysfunction associated with sepsis.

The illustration depicts the dysregulation at the levels of the innate immune response (complement, neutrophils, monocytes-macrophages) as well as the adaptive immune response (T cells and B cells) that characterizes the immunopathology observed in the setting of sepsis.

Figure 2:. Representative monocyte HLA-DR expression before and after GM-CSF treatment in sepsis.

This is an example of polychromatic flow-cytometry utilized to assess monocyte-associated HLA-DR expression pre and post GM-CSF treatment in a sepsis patient. Briefly, whole blood samples from a patient and commercially available flow-cytometry control samples (Streck, Omaha, NE) were stained with fluorochrome-conjugated monoclonal antibodies targeting the CD45, CD3 and HLA-DR surface markers, and hierarchical gating was utilized to evaluate HLA-DR expression on monocytes. Monocytes were identified based on CD45 expression and light scatter characteristics (side-scatter [SSC]) (left panel). Surface expression of HLA-DR on monocytes is demonstrated by utilizing the stacked histogram plot (right panel). The numerical values in the plot depict the frequency of monocytes expressing HLA-DR and response post GM-CSF therapy. Laboratory assays done under IRB-approved protocol at Lurie Children’s.

Figure 3:. Targeted immunomodulatory therapies in sepsis.

Schematic depicting therapies trialed to target specific areas of immune dysregulation in sepsis. Treg: regulatory T cell, HLA-DR: human leukocyte antigen-DR, IFN: interferon, TNF: tumor necrosis factor, IL: interleukin, PD: programmed cell death, PDL: programmed cell death ligand.